Traditionally, fluids aimed for parenteral administration to the blood stream of patients have been packaged in glass containers. There has, however, been much industrial efforts devoted to find alternative polymeric materials which are less resource consuming, cheaper and more convenient to handle than glass.
As discussed in, for example the International patent application WO 94/19186 (in the name of Pharmacia AB and Wipak Vihury Oy), it is considerable amount of technical problems that must be solved before a polymeric material with satisfying properties for storing parenterally injectible fluids is obtained. The material and container made thereof should be capable of withstanding different sterilization techniques without losing important characteristics, such as forming both an oxygen barrier and moisture barrier against the environment. They shall be compatible with fluids to be stored, even after a long term storage and even if the fluids contain lipophilic constituents that might lead to migration and dissolution of unwanted compounds from the polymeric matrix. In addition, the materials must be possible to weld together and be printable and maintain their flexibility and other mechanical properties, as well as their aesthetic appearance (i.e. transparency) after the sterilization procedure. It is also an important requirement that such a container shall be sterilized as a final step, after being filled and assembled, to provide the highest possible safety for the patients. It has been found that not even the highly sophisticated multilayer films according to the mentioned WO 94/19186 will be completely capable of meeting the highly rigorous requirements of keeping an oxygen barrier, when it is desired to store such sensitive fluids as lipid emulsions containing polyunsaturated fatty acids, for such a long time as several months in room temperature after autoclavation in a single package.
However, so far it has not been regarded as possible to obtain all the desirable properties combined in a single material and arrive with a cheap, convenient construction which also is environment friendly and possible to recycle by its manufacturer. For example, in the U.S. Pat. No. 5,176,634 to McGaw Inc., it is disclosed a flexible container having three chambers separated by frangible seals, in which diluents and medicaments are separately stored until the seals are ruptured to mix the contents together for delivery to a patient. If it is necessary to form a sheltering barrier against environmental oxygen for a stored product, this patent suggests the introduction of an aluminum foil as a complement to the multilayered polymeric material of the container. Such a mixture of metal and polymers in the same package, would however not, be desirable from an environmental viewpoint, since a recollection and recycling of the material would be difficult. Furthermore, the U.S. Pat. No. 5,176,634 does not particularly teach containers that can be steam sterilized after their assembly and filling which is a precondition for container systems for long term storage of parenteral nutrients intended to substitute glass bottles. The container disclosed in U.S. Pat. No. 5,176,634 obviously will be less suitable for separate storage of two or more steam sterilized parenteral nutrients.
The U.S. Pat. No. 4,997,083 in the name of Vifor S.A. discloses a flexible three-chamber bag for separate storage of lipids, amino acid and sugar to be mixed within the bag and used parenterally. For the mixing of the ingredients, transfer passages between the chambers are opened from the outside by the user. It is a drawback with this type of containers that the mixing will be relatively slow and complicated, especially if all the chambers are filled to a high degree and liquid must be pushed back and forth through the passages in order to complete the mixing procedure. If the lower mixing chamber is made large enough to comprise the volume of all three constituents during the mixing, the lower chamber must be filled with a large head space which gives disadvantages during the sterilization and storage of the products and leads to a poor utilization of the polymeric packaging material. Furthermore, the polymerized materials suggested to constitute the flexible bag in the U.S. Pat. No. 4,997,083 will not be sufficient to keep the nutrients from oxidative degradation after long term storage.
The International patent application WO 95/26117 in the name of Fresenius AG discloses a more convenient type of multi-chamber bag wherein the partition between the chambers are made by a weak welding possible to rupture to immediately obtain a large mixing cross-sectional area without the risk of tearing away parts of the breakable means. Even if this bag is made of a specifically designed multilayer foil having a sealant layer capable of forming different type of weldings at different temperatures, it will not be able to form a satisfactory oxygen barrier to protect highly sensitive contents during long time storage after autoclavation. Also its construction having filling tubes in the permanent seams sealing the chambers constitutes a risk of leakages and may cause problems if it is desired to have an additional airtight enclosure. This container therefore seems less suitable as a three-chamber container for joint separate storage of lipid emulsion, carbohydrates and amino acid solutions. Moreover, the exemplified incorporation of a paraffin oil in the multilayered material, would hardly be compatible with the storage of lipid emulsion when considering the risk for migration.
Also the British patent specification GB 2 134 067, in the name C.R. Bard Inc., discloses a flexible three compartment package having rupturable seals between the chambers to enable mixing before dispensing of its contents. This package will, however not, for material reasons be suitable for parenteral medical products, such as infusible nutrients.
The U.S. Pat. No. 4,872,553 in the name of Material Technology Engineering teaches a single chamber container made of polymers, suitable for storing an amino acid solution aimed for parenteral nutrition, while the U.S. Pat. No. 4,998,400, assigned to the same company, discloses a method of making such a container. It is disclosed how to fill and seal an inner primary container in an inert atmosphere, whereupon it is enclosed in an outer envelope together with a deoxidizer and autoclaved. The inner container consists of a linear low density polyethylene while the outer envelope consists of a three-layered laminated film formed of an outer nylon layer, a middle layer of an ethylene-vinyl alcohol copolymer and an inner polypropylene layer. Such a material will, however, not be possible to steam sterilize with maintained quality at 121.degree. C. as required by the European Pharmacopoeia. However, not even such a container is likely to be entirely successful to provide a barrier for atmospheric oxygen after autoclavation and during long-term storage, up to 12 months or more, of more sensitive fluids, like lipid emulsions based on triglyceridic oils rich in polyunsaturated fatty acids and certain amino acids. The teachings of U.S. Pat. No. 4,998,400 indicates that the outer envelope risks to lose important characteristics by the steam sterilization. In one embodiment it is suggested that only the inner container shall be autoclaved. The inner container is thereafter cooled in an inert atmosphere and finally enclosed with the oxygen impermeable envelope. Such a process is not completely satisfying since it for rational reasons is desirable to make the sterilization step on the finally filled and assembled container. In another embodiment it is suggested that the finally assembled and sealed container is autoclaved. However, in order to retain the oxygen barrier after the autoclavation an extra drying process must be introduced in order to remove absorbed moisture from outer envelope.
The European Patent Application EP 0 639 364 by Otsuka Pharm. Factory Inc. discloses another recent flexible multi-chamber bag for storage of oxygen sensitive agents. This bag is preferably useful for storing degradable powder formed drug and its diluent in separate chambers. The chamber filled with the oxygen sensitive powder is covered with an oxygen barrier forming envelope which is sealed in a controlled atmosphere by weldings to the bag. A drawback with the containers exemplified in this application is that they may not withstand autoclavation after their final assembly.
It is obvious that the construction of a flexible multi-chamber container intended to substitute glass bottles for storing parenteral nutrients, such as lipid emulsions is a highly complex development process. A careful consideration must be taken to the capacity of the materials of being autoclavable with maintained characteristics, to their capacity of providing a barrier against environmental oxygen and water vapor, while at the same time it must be easy to process to a functional multi-chamber container, for example with conventional welding technology and comply with the demands of being possible to recollect and recycle in one single, simple process. For the parts of the container in contact with the stored, often lipophilic substances, it is a requirement that potentially hazardous agents must not be allowed to migrate into the parenteral product. Conventionally employed polymers in medical packages, like polyvinyl chlorides (PVC), and other polymers containing migrating plasticizers therefore can not be considered. Nevertheless, these polymeric materials have a higher permeability to oxygen than glass bottles which makes them unsuitable for long-term storage of especially sensitive fluids. Moreover, the material must have an aesthetically attractive appearance with a transparency that do not deteriorate after sterilization and storage. In addition, the material must allow printing of instructions and filling levels without migration of the printing ink. It is also important that the material maintains all the mechanical characteristics, such as flexibility and strength, after the sterilization independently, if it is performed by steam or radiation. Besides the important material properties, the container must be convenient to handle when mixing the stored products and provide a high degree of safety for the patient, both when considering the manufacture of the container and its handling by the user either in the home of a patient or at a hospital.
It is an object of the present invention to provide a flexible container of substantially made of a polymeric material with an improved barrier against environmental oxygen and moisture which also is capable of withstanding sterilization by means of high pressure steam (autoclavation) or irradiation essentially without losing any such barrier capacity or other important characteristics including flexibility or transparency, so even stored agents of high oxygen susceptibility may be stored for long periods with maintained integrity.
It is also an object of the present invention to provide a flexible container for separated long term storage of such agents that are easily perishable when stored together in their final parenterally administerable form and provide the container with means for mixing such agents aseptically within the container to an injectible fluid.
It is a particular object of the present invention to provide such a container for storing parenteral nutrition components separately, i.e. a lipid emulsion, a carbohydrate solution and an amino acid solution, and subsequently, just before parenteral administration, combine them to a homogenous fluid nutrient mixture.
It is another particular object of the present invention to prolong the possible storage period both in a cold environment and in room temperature for sensitive fluids aimed for total parenteral nutrition to overcome the problem of short shelf-life of such products.
It is still another object of the invention to provide a container with the capacity of separately storing several components filled in ready-made inner container which has a minimized number of potential sites where leakages can appear.
It is a further object of the present invention to provide such containers which are safe and convenient to handle and which minimize the risks for erroneous handling and contamination during all the steps necessary to obtain a parenterally administerable fluid of a predetermined quality.
It is a still further object of the present invention to provide such containers that are cheap and environment friendly by being to a high extent made of such polymeric materials which are possible to recollect and recycle together without an inconvenient dismembering of different container parts.
It is also an object of the present invention to provide a process for manufacturing such filled containers that are sterilized as a last stage after being assembled and filled, wherein the filling process is performed in a manner that avoids permanent, potentially leaking filling ports.
These objects of the present invention, as well as other obvious advantages demonstrated in this text, are attained by the appended claims.